The present invention relates to novel naphthalamides useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are dopaminergic agents useful as antipsychotic agents for treating psychoses such as schizophrenia.
Dopamine (DA) D2 antagonists are established as antipsychotic agents. More recently, the dopamine D3 receptor has been identified and seems to mediate some of the effects of antipsychotic agents (Schwartz Jean-Charles, et al., The Dopamine D3 Receptor as a Target for Antipsychotics. In Novel Antipsychotic Drugs, Meltzer H. Y., Ed., Raven Press, N.Y., 1992, p. 135-144). The localization of the dopamine D3 receptor in the limbic area of the brain suggests that a selective D3 antagonist should retain the antipsychotic activity of D2 antagonists but not have their neurological side effects (Sokoloff P., et al., Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347:146 (1990); Sokoloff P., et al., Localization and Function of the D.sub.3 Dopamine Receptor, Arzneim.-Forsch./Drug. Res., 42(1):224, (1992)).
The compounds of the present invention are also useful for the treatment of disorders which respond to dopaminergic blockade which include psychotic depression, substance abuse (Caine S. B. and Koob G. F., Modulation of Cocaine Self-Administration in the Rat Through D-3 Dopamine Receptors, Science, 260:1814 (1993)), and compulsive disorders (Goodman W. K., et al., The role of serotonin and dopamine in the pathophysiology of obsessive compulsive disorder, International Clinical Psychopharmacology, 7(Supp. 1):35 (1992)).
European Published Patent Application EP 539 281 A1 discloses a series of naphthamide derivatives of the formula: ##STR1## X=H, Cl, Br, amino, aminoalkyl, aminosulphamoyl, S-containing group (such as thiocyanato, alkylthio, alkylsulphinyl, or alkylsulphonyl), methoxy, nitro, cyano, or electron attracting group;
Y=alkyl or alkenyl; PA0 Z=a residue derived from 2-aminomethyl-N-alkyl-pyrrolidine, 2-aminoethyl-N,N-diethylamine, 2-amino-ethyl-morpholine, 2-aminoethyl-N,N-dibutylamine, 4-amino-N-butyl (or N-benzyl)-piperidine, or 2-aminoethyl pyrrolidine; PA0 R=H or methoxy; PA0 (A) When W is a carbocyclic or heterocyclic ring, then A and B=H or A+B=carbonyl; and PA0 (B) When W is opt. substd. methylene, then PA0 A+B=carbonyl and n.sup.1 and n.sup.2 are not both zero. PA0 R.sup.2 is halogen, PA0 R.sup.3 is hydrogen, PA0 R.sup.4 is hydrogen or
useful as antipsychotics, antidepressants, psycho-stimulants, antiautistic agents, anti-Parkinson agents, and antihypertensives.
U.S. Pat. No. 5,254,552 discloses a series of aryl and heteroaryl piperazinyl carboxamides of the formula: ##STR2## wherein R.sup.1 is 1-adamantyl, 3-methyl-1-adamantyl, 3-noradamantyl, unsubstituted or substituted 2-indolyl, 3-indolyl, 2-benzofuranyl, or 3-benzo-furanyl wherein the substituents are selected from lower alkyl, lower alkoxy, and halo; R.sup.2 is unsubstituted or substituted phenyl, benzyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the substituents are selected from lower alkyl, lower alkoxy, trifluoromethyl, and halo; R.sup.3 is H or lower alkyl of 1 to 3 carbon atoms; n is the integer of 0 or 1; and m is the integer from 2 to 5 and the pharmaceutically acceptable salts thereof having central nervous system activity and useful as potential anxiolytic-antidepressant agents.
International Published Patent Application WO 93/21179 discloses a series of amidoalkyl- and imidoalkyl-piperazines of the Formula I: ##STR3## wherein R=H or phenyl;
m=3-8; PA1 R.sub.4 =NO.sub.2 or NR.sub.7 R.sub.8 and is in m- or p-position; PA1 R.sub.7, R.sub.8 =H or 1-3 C alkyl; PA1 R.sub.5 =H, halo or CF.sub.3 and is in o-, m-, or p-position; PA1 R.sub.6 =halo or CF.sub.3 and is o-, m-, or p-position; PA1 W=aromatic ring (opt. substd.), a heterocyclic ring, a carbocyclic ring, or an opt. substd. methylene gp.; PA1 A=H, OH, halo, CF.sub.3, 1-3 C alkyl, 1-3 C alkoxy, phenyl, or phenoxy; PA1 B=H; or PA1 A+B=carbonyl; PA1 n.sup.1 =0 or 1; PA1 n.sup.2 =0 or 1. PA1 alkyl, PA1 alkoxy, PA1 thioalkoxy, PA1 hydroxy, PA1 amino, PA1 alkylamino, or PA1 dialkylamino; PA1 nitro, PA1 cyano, PA1 SO.sub.2 NH--, PA1 alkyl, or PA1 alkoxy; PA1 hydroxy, or PA1 methoxy; PA1 alkyl; and PA1 R.sup.5 is aryl, PA1 2-, 3-, or 4-pyridinyl, PA1 2-, 3-, or 4-pyridinyl substituted by halogen, PA1 2-benzothiazolyl, PA1 2-benzoxazolyl, PA1 3-benzo [b]thienyl, PA1 7-benzo [b]furanyl, PA1 2-, 3-, 4-, 5-, 6- , or 7-indolyl, PA1 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl or 1-benzisothiazolyl; or
Provided that:
However, the naphthamides disclosed in EP 539 281 A1, and the aryl and heteroaryl piperazinyl carboxamides disclosed in U.S. Pat. No. 5,254,552 and the amidoalkyl- and imidoalkyl-piperazines disclosed in WO 93/21179 do not disclose or suggest the combination of structural variations of the compounds of the present invention described hereinafter.